SYMCARD - Antiplatelet in ACS.pptx
- 1. Antiplatelet Therapy inACS MASRUL SYAFRI, MD, PhD MAT-ID-2101140-v1.0 (09/2021)
- 2. Mechanism Antithrombotic Therapy RodriguezF, Harrington RA. N Engl J Med. 2021;384(5):452-460.
- 3. Management of AntithromboticTherapy after Acute Coronary Syndromes ACS, acute coronary syndrome; DOAC, direct oral anticoagulant; mo, month(s). Rodriguez F, Harrington RA. N Engl J Med. 2021;384(5):452-460.
- 4. DAPT choice forelder patients? TRITON-TIMI 38 trial and PLATO trial showed superiority of prasugrel and ticagrelor versus clopidogrel in reducing cardiovascular death, MI, and stroke. With increasing age, patients have higher risks of bleeding and thrombotic events. TRITON-TIMI 38 did not show a net clinical benefit of prasugrel in the subgroup of older patients (aged ≥75 years), due to higher rates of bleeding. In the PLATO trial, ticagrelor related bleeding occurred more frequently than did clopidogrel related bleeding, especially in older patients. Rationale Objective To determine the optimal P2Y12 inhibitor in older patients with NSTE-ACS by assessing the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in patients aged 70 years or older. MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome. Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
- 5. Study design andmethods N = 1011 Within 72 hours after admission Clopidogrel 75mg QD (n = 506) Ticagrelor 90 mg BID or Prasugrel 10 mg QD (n = 505) Clopidogrel 75mg QD (n = 500) Ticagrelor 90 mg BID or Prasugrel 10 mg QD (n = 502) Randomization 1:1 3 dropped out 6 dropped out Endpoints assessment ITT analysis Treatment for 12 months An open-label, randomized trial targeting patients aged 70 years or older, presenting with a NSTE-ACS Gimbel M, et al. Lancet. 2020;395(10233):1374-81. BID, twice daily; QD, once daily; ITT, intention to treat; NSTE- ACS, non-ST-elevation acute coronary syndrome.
- 6. Study endpoints Presentation title| XX Month XXX BARC, bleeding academic research consortium; PLATO, platelet inhibition and patient outcomes; TIMI, thrombolysis in myocardial infarction. Bleeding outcomes PLATO bleeding TIMI bleeding BARC bleeding Thrombotic outcomes All-cause death Myocardial infarction Stroke Cardiovascular death Ischemic stroke Unstable angina Transient ischemic attack Stent thrombosis Urgent revascularization Primary endpoint • Bleeding outcome: PLATO bleeding* major & minor • Net clinical benefit outcome: composed of all-cause death, myocardial infarction†, stroke‡ and PLATO major or minor bleeding Secondary endpoint • All thrombotic outcomes • All bleeding outcomes * Defined according to the criteria of the PLATO trial † Defined according to the third universal definition of myocardial infarction ‡ Defined as an acute new neurological deficit ending in death or lasting >24 h not due to another readily identifiable cause such as trauma Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
- 7. Baseline Characteristics Gimbel M,et al. Lancet. 2020;395(10233):1374-81. • The baseline characteristics were well balanced between both treatment groups
- 8. Results CI, confidence interval;HR, hazard ratio. Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
- 9. Conclusions MI, myocardial infarction;NSTE-ACS, non-ST-elevation acute coronary syndrome. Gimbel M, et al. Lancet. 2020;395(10233):1374-81.
- 10. PHILO (TW/JP/KR): TrialDesign • Design: Multicenter, double-blind, randomized trial • Patient type: Patients with ACS, and all were planned to undergo PCI and randomized within 24 h of symptom onset • Ethnicity: 801 East Asians (Japanese, n = 721; Taiwanese, n = 35; South Korean, n = 44; unknown ethnicity, n = 1) ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; bid: twice daily; qd: once daily Concomitant Aspirin 75-100 mg Goto S, et al. Circ J. 2015;79(11):2452-2460. Group Patient no. Loading dose Maintenance dose Ticagrelor 401 180 mg 90 mg bid Clopidogrel 400 300 mg 75 mg qd
- 11. PHILO : EfficacyResults • In ACS patients from Japan, Taiwan and South Korea, event rates of primary safety and efficacy endpoints were higher, albeit not significantly, in ticagrelor-treated patients compared with clopidogrel-treated patients. Data given as n (%). ACS, acute coronary syndrome; ATE, arterial thromboembolic event; CV, cardiovascular; MI, myocardial infarction; RI, recurrent cardiac ischemia; SRI, serious recurrent ischemia; TIA, transient ischemic attack. Primary and Secondary Efficacy Endpoints Ticagrelor 90 mg b.i.d. (n = 401) Clopidogrel 75 mg o.d. (n = 400) HR (95% CI) Primary Composite of CV death/MI (excluding silent MI)/stroke 36 (9.0) 25 (6.3) 1.47 (0.88 – 2.44) Post-hoc Composite of CV death/spontaneous MI/stroke 18 (4.5) 13 (3.3) 1.39 (0.68 – 2.85) Secondary Composite of all-cause mortality/MI (excluding silent MI)/stroke 37 (9.2) 25 (6.3) 1.51 (0.91 – 2.50) Composite of CV death/total MI/stroke/RI (including SRI)/TIA/Other ATE 38 (9.5) 32 (8.0) 1.20 (0.75 – 1.93) MI (excluding silent MI) 24 (6.0) 15 (3.8) 1.63 (0.85 – 3.11) Peri-procedure MI 18 12 - Spontaneous MI 6 3 - CV death 9 (2.2) 7 (1.8) 1.28 (0.48 – 3.45) Stroke 9 (2.2) 6 (1.5) 1.50 (0.54 – 4.23) All-cause mortality 10 (2.5) 7 (1.8) 1.42 (0.54 – 3.74) Goto S, et al. Circ J. 2015;79(11):2452-2460.
- 12. PHILO (TW/JP/KR): MajorAdverse Cardiovascular Event CV, cardiovascular; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. 1. Goto S, et al. Circ J. 2015;79(11):2452-2460 2. Wallentin L, et al. N Engl J Med. 2009;361:1045-57 PLATO2 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI) CV Death, MI or Stroke 9.8 11.7 0.84 (0.77 - 0.92) Myocardial Infarction 5.8 6.9 0.84 (0.75 - 0.95) PHILO1 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI) CV Death, MI or Stroke 9.0 6.3 1.47 (0.88 - 2.44) Myocardial Infarction 6.0 3.8 1.63 (0.85 - 3.11)
- 13. Major + MinorBleeding *PLATO study bleeding criteria CI, confidence interval; HR, hazard ratio PLATO2 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI) Major Bleeding 11.6 11.2 1.04 (0.95 - 1.13) Major and Minor Bleeding 16.1 14.6 1.11 (1.03 - 1.20) PHILO1 (%) Ticagrelor Clopidogrel HR for Ticagrelor (95% CI) Major Bleeding 10.3 6.8 1.54 (0.94 - 2.53) Major and Minor Bleeding 23.8 14.7 1.72 (1.23 - 2.40) 1. Goto S, et al. Circ J. 2015;79(11):2452-2460 2. Wallentin L, et al. N Engl J Med. 2009;361:1045-57
- 14. Balancing antithrombotic treatmentpost PCI Intrinsic (in blue): patient’s characteristics, clinical presentation & comorbidities) and extrinsic (in yellow: co-medication & procedural aspects) variables influencing the choice, dosing, and duration of antithrombotic treatment. DAPT de-escalation Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79.
- 15. Consensus on SwitchingADP Blockers: Definitions Type of Pharmacodynamic Switch Type of Drug Class Switch Potential for DDI Oral* Escalation Clopidogrel to prasugrel Intraclass No Clopidogrel to ticagrelor Interclass No De-escalation Prasugrel to clopidogrel Intraclass No Ticagrelor to clopidogrel Interclass Yes Change Prasugrel to clopidogrel Interclass No Ticagrelor to clopidogrel Interclass Yes Intravenous Bridge Clopidogrel to cangrelor Interclass No Prasugrel to clopidogrel Interclass No Ticagrelor to clopidogrel Interclass No Transition Cangrelor to clopidogrel Interclass Yes Cangrelor to prasugrel Interclass Yes Cangrelor to ticagrelor Interclass No Table 2. Modalities of Switching Between P2Y12 Receptor Inhibitors and Potential for DDI DDI indicates drug-drug interaction. *Switching between oral agents may be classified according to relationship from the index event a defined as acute (<24 hours), early (1–<30 days), late (>30 days–1 year), and very late (>1 year). Angiolillo DJ, et al. Circulation. 2017;136(20):1955-1975.
- 16. Ticagrelor (n = 9235),n (%) Clopidogrel (n = 9186), n (%) Hazard ratio (95% CI) P-value Non-CABG-related major bleeding First 30 days on study drug 224 (2.47) 199 (2.21) 1.123 (0.928–1.360) 0.23 After 30 days on study drug 149 (2.17) 113 (1.65) 1.338 (1.048–1.708) 0.02 + Adjusting by bleeding events in first 30 days 1.329 (1.041–1.698) 0.02 + Adjusting by PCI in first 30 days 1.332 (1.043–1.701) 0.02 Non-procedure-related major bleeding First 30 days on study drug 112 (1.25) 93 (1.05) 1.201 (0.912–1.581) 0.19 After 30 days on study drug 129 (1.90) 89 (1.30) 1.471 (1.123–1.927) 0.01 + Adjusting by bleeding events in first 30 days 1.466 (1.119–1.920) 0.01 + Adjusting by PCI in first 30 days 1.469 (1.121–1.925) 0.01 Table 5. Landmark analyses: first 30 days on study drug vs. after 30 days on study drug CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention. Background: Early vs. late events in PLATO Becker RC, et al. Eur Heart J. 2011;32(23):2933-44;
- 17. Background: Real-Life Dataon DAPT de-escalation 15 % 28 % DAPT De-escalation Clinical & socio- economic factors Zettler ME, et al. Am Heart J. 2017;183:62-68.
- 18. SCOPE: Registry dataon unguided DAPT de-escalation De Luca L, et al. EuroIntervention. 2017;13(4):459-466.
- 19. Evolution of recommendationson DAPT de-escalation ESC 2018 guidelines on myocardial revascularization – First mentioning of DAPT de-escalation1: ESC 2020 guidelines on NSTE-ACS – Expansion of DAPT de-escalation recommendation: Inclusion of unguided DAPT de-escalation Inclusion of genotyping 1. Neumann FJ. et al. European Heart Journal (2018) 00, 1–96. 2. Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79
- 20. Clinical variables favoringDAPT de-escalation Two clinical approaches for DAPT de-escalation: 1) Pro-active DAPT de-escalation: Preventive de-escalation BEFORE the occurrence of adverse events (e.g. bleeding) 2) Re-active DAPT de-escalation: Change of treatment AFTER the occurrence of adverse events (e.g. bleeding) Prior Major Bleeding Anemia Clinically Significant Bleeding on Potent P2y12 Inhibitors High Bleeding Risk Defined by Bleeding Risk Scores Socio-Economic Factors Favouring the Lower Costs of Clopidogrel Side Effects on Prasugrel And Ticagrelor, Especially Dyspnea on Ticagrelor Need for Triple Treatment Due to New Onset Atrial Fibrillation or Left Ventricular Thrombus After Myocardial Infarction Table 2. Variables that could be considered for favouring de-escalation of dual antiplatelet therapy. Claassens DM, Sibbing D. J Clin Med. 2020;9(9):2983.
- 21. Evolving paradigms © D. Capodanno Capodanno D,Angiolillo DJ, et al. Nat Rev Cardiol. 2018;15:480-496 TASS CAPRIE PERFORM CURE CREDO CLARITY COMMIT CHARISMA TRACER ATLAS ACS 2 COMPASS GEMINI ACS SOCRATES PEGASUS ENTRUST STOP-DAPT 2 SMART-CHOICE GLOBAL LEADERS THEMIS AUGUSTUS 1989 1996 2001 2002 2005 2006 2011 2012 2013 2015 2016 2017 2018 2019 2020 WOEST RE-DUAL PIONEER TWILIGHT PCI Prior CVA Prior MI Stable CVD ACS TRA-2P Trials of add-on antithrombotics Trials of aspirin replacement Trials of aspirin-free strategies TICO
- 22. Dropping aspirin, why? © D. Capodanno 1.Bleeding risk Increased risk of intracranial and extracranial bleeding, especially in combination with other antithrombotic drugs 2. Novel drugs The availability of new compounds with potent antithrombotic efficacy could make the use of aspirin no longer necessary 3. Risk reduction Contemporary drugs favorably alter the baseline individual risk of cardiovascular events, translating the relative benefits of aspirin into smaller absolute effects Capodanno D, Angiolillo DJ, et al. Nat Rev Cardiol. 2018;15:480-496
- 23. Effect of 1-MonthDAPT Followed by Clopidogrel vs 12-Month DAPT After PCI OPEN-LABEL, MULTICENTER, NONINFERIORITY RANDOMIZED TRIAL 1 month of DAPT (followed by clopidogrel monotherapy) 12 months of DAPT (aspirin and clopidogrel) CV death, MI, stroke, definite ST, major or minor bleeding at 12 mo 2.4% 3.7% Major or minor bleeding 0.4% 1.5% 1 month of DAPT followed by clopidogrel monotherapy resulted in a significantly lower rate of NACE Hazard ratio 0.64; 95% CI 0.42-0.98; PNI<0.001; PSUP=0.04 Watanabe H, et al. JAMA. 2019;321:2414-2427 P=0.004 STOPDAPT-2 3,045 Patients undergoing percutaneous coronary intervention N=1,523 N=1,522 ►
- 24. Effect of P2Y12Inhibitor Monotherapy vs DAPT in Patients Undergoing PCI OPEN-LABEL, MULTICENTER, NONINFERIORITY RANDOMIZED TRIAL 3 months of DAPT (followed by clopidogrel monotherapy) 12 months of DAPT (aspirin and clopidogrel) All-cause death, MI, or stroke at 12 mo 2.9% 2.5% BARC 2 to 5 type bleeding 2.0% 3.4% P2Y12 inhibitor monotherapy after 3 months of DAPT resulted in noninferior rates of MACCE Difference 0.4%; 1-sided 95% CI, -∞% to 1.3%; PNI=0.007 Hahn JY, et al. JAMA. 2019;321:2428-2437 P=0.02 SMART-CHOICE 2,993 Patients undergoing percutaneous coronary intervention N=1,495 N=1,498 ►
- 25. Meta-analysis O’ Donoghue ML,et al. Circulation. 2020;142:538–545 Bleeding MACE P2Y12 inhibitor SAPT preferred P2Y12 inhibitor SAPT preferred DAPT preferred DAPT preferred -40%
- 26. Recommendations Class Level Afterstent implantation in patients undergoing a strategy of DAPT, stopping aspirin after 3-6 months should be considered, depending on the balance between the ischaemic and bleeding risk. IIa A Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79 2020 ESC Guidelines for ACS Without ST Elevation Antiplatelet Therapy
- 27. Duration of DAPT Time 1month 3 months 6 months 12 months DAPT Duration A T A T C P Aspirin Clopidogrel Prasugrel Ticagrelor Bleeding risk 12-mo DAPT A C A P A T or or A P A C DAPT >12 mo A T or DAT >12 mo A R R Rivaroxaban T A C A A C LOW HIGH VERY HIGH Ischemic risk NSTE-ACS Collet JP, et al. Eur Heart J. 2020;ehaa575:1-79 C
- 28. Ongoing trials Modified fromCao D, et al. Eur Heart J. 2021;42:339-351 Study name n Study population Study intervention Primary outcome(s) OPT-BIRISK 7,700 ACS and PCI (9-12 mo of DAPT) Clopidogrel SAPT BARC 2-5 at 9 mo SMART-CHOICE 3 5,000 Prior PCI (≥12 months) Clopidogrel SAPT MACCE at 12 mo STOPDAPT-2 ACS 3,008 ACS and PCI Clopidogrel SAPT NACE at 12 and 60 mo NEOMINDSET 3,400 ACS and PCI Prasugrel or Ticagrelor SAPT MACCE at 12 mo BARC 2-5 at 12 mo A-CLOSE 3,200 PCI (12 mo of DAPT) Clopidogrel SAPT NACE between 12 and 36 mo IVUS-ACS and ULTIMATE-DAPT 3,486 ACS and PCI Ticagrelor SAPT BARC 2-5 and MACCE between 1 and 12 mo SMART-CHOICE II 1,520 PCI (12 mo of DAPT) Clopidogrel or low-dose ticagrelor SAPT MACCE between 12 and 36 mo HOST-EXAM 5,530 PCI (12±6 mo of DAPT) Clopidogrel SAPT NACE at 24 mo
- 29. Summary • ACS Day1 potent antiplatelet is not always better in : • For elder (age＞75) patients, high potency DAPT may result in higher bleeding rate without definite clinical benefit • For East Asian patients, several studies focusing on the population favored the use of clopidogrel • ACS Month 1 DAPT de-escalation (guided or unguided) is considered as an optional treatment regimen especially for ACS patients deemed unsuitable for potent DAPT • DAPT de-escalation is common practice after ACS-PCI (STEMI & NSTE-ACS) and can be utilized in a pro- or re-active manner • Triggers are bleeding events/presumed high bleeding risk, drug compliance, side-effects of ticagrelor/prasugrel as well as socio-economic aspects • Recent ESC guidelines have included respective IIb recommendations (case-by-case decision) • Up to Year 1 Single antiplatelet therapy • The evidence supporting the aspirin-free strategy up to 1 year after PCI is accumulating in parallel with pharmacodynamic studies suggesting that there is little apparent pharmacodynamic benefit in adding aspirin to a potent P2Y12 inhibitor. • This strategy should not be intended to replace evidence-based strategies of intensified antithrombotic therapy for patients at high thrombotic risk and low bleeding risk.